Cis-substituted aminocyclopropane derivatives

ABSTRACT

The present invention is to provide an antimicrobial agent having high safety as well as potent antimicrobial activity on broad range of microorganisms.  
     A compound represented by the following formula, its salt and their hydrates:  
                 
 
     wherein R 1  and R 2  each independently represents a hydrogen atom or an alkyl group; n represents an integer of 1 to 3; R 3  represents an alkyl group, an alkenyl group, a halogenoalkyl group, a cycloalkyl group, an aryl group, a heteroaryl group, an alkoxyl group or an alkylamino group; R 4  represents a hydrogen atom or an alkylthio group; R 5  represents a hydrogen atom, an amino group, a hydroxyl group, a thiol group, a halogenomethyl group, an alkyl group, an alkenyl group, an alkynyl group or an alkoxyl group; X 1  represents a halogen atom or a hydrogen atom; and A represents a nitrogen atom or a partial structure represented by formula (II):  
                 
 
     wherein X 2  represents a hydrogen atom, an amino group, a halogen atom, a cyano group, a halogenomethyl group, a halogenomethoxyl group, an alkyl group, an alkenyl group, an alkynyl group or an alkoxyl group; and Y represents a hydrogen atom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group, an alkyl, an alkoxymethyl group or a phenylalkyl group.

TECHNICAL FIELD

[0001] This invention relates to an antimicrobial compound useful as adrug for humans, animals or fishes or an antimicrobial preservative andan antimicrobial agent or preparation containing the same.

BACKGROUND ART

[0002] Since the discovery of Norfloxacin, improvements have been addedto synthetic quinolone antimicrobial agents in antimicrobial activityand in pharmacokinatics, and many compounds have been launched forclinical use as a chemotherapeutic agent effective on all most allsystemic infectious diseases.

[0003] However, low sensitive bacteria resistant to the syntheticquinolone antimicrobial agents have recently been increasing in theclinical field. For example, bacteria resistant to drugs other thansynthetic quinolone antimicrobial agents have come to acquire resistanceto synthetic quinolone antimicrobial agents, as exemplified byStaphylococcus aureaus insensitive to β-lactam antibiotics (MRSA).Therefore, more effective drugs have been keenly demanded in the fieldof clinics.

[0004] Further, it has been revealed that synthetic quinoloneantimicrobial agents tend to involve side effects, such as induction ofconvulsion in a combined use with a non-steroid antiinflammatory agent,and phototoxicity. Therefore, development of safer synthetic quinoloneantimicrobial agents has been sought.

DISCLOSURE OF THE INVENTION

[0005] In the light of these circumstances, the inventors have conductedextensive investigation for the purpose of providing excellent compoundsfulfilling the above demands. As a result, they have found thatcis-substituted aminocyclopropane derivatives represented by thefollowing formula (I) and their salts have broad antimicrobial spectra,exhibiting potent antimicrobial activity particularly on Gram positivebacteria, especially quinolone-resistant bacteria including MRSA, andalso show satisfactory in pharmacokinatics and safety.

[0006] The present invention relates to a compound represented byformula (I) shown below, its salt and their hydrates:

[0007] wherein R¹ and R² each independently represents a hydrogen atomor an alkyl group having 1 to 6 carbon atoms which may be substitutedwith one or more substituents selected from the group consisting of ahydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbonatoms, and an alkyloxy group having 1 to 6 carbon atoms; n represents aninteger of 1 to 3; Q represents a partial structure having formula:

[0008] wherein R³ represents an alkyl group having 1 to 6 carbon atoms,an alkenyl group having 2 to 6 carbon atoms, a halogenoalkyl grouphaving 1 to 6 carbon atoms, a substituted or unsubstituted cycloalkylgroup having 3 to 6 carbon atoms, a substituted or unsubstituted arylgroup, a substituted or unsubstituted heteroaryl group, an alkoxyl grouphaving 1 to 6 carbon atoms, or an alkylamino group having 1 to 6 carbonatoms; R⁴ represents a hydrogen atom or an alkylthio group having 1 to 6carbon atoms; R³ and R⁴ may be taken together with part of the motherskeleton to which they are bonded to form a cyclic structure that maycontain a sulfur atom as a ring constituting atom and/or may besubstituted with an alkyl group having 1 to 6 carbon atoms; R⁵represents a hydrogen atom, an amino group, a hydroxyl group, a thiolgroup, a halogenomethyl group, an alkyl group having 1 to 6 carbonatoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl grouphaving 2 to 6 carbon atoms or an alkoxyl group having 1 to 6 carbonatoms, in which the amino group may be substituted with one or moresubstituents selected from the group consisting of a formyl group, analkyl group having 1 to 6 carbon atoms, and an acyl group having 2 to 5carbon atoms; X¹ represents a halogen atom or a hydrogen atom; and Arepresents a nitrogen atom or a partial structure represented by formula(II):

[0009] wherein X² represents a hydrogen atom, an amino group, a halogenatom, a cyano group, a halogenomethyl group, a halogenomethoxyl group,an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, or analkoxyl group having 1 to 6 carbon atoms, in which the amino group maybe substituted with one or more substituents selected from the groupconsisting of a formyl group, an alkyl group having 1 to 6 carbon atomsand an acyl group having 2 to 5 carbon atoms; and X² and R³ may be takentogether with part of the mother skeleton to which they are bonded toform a cyclic structure that may contain an oxygen atom, a nitrogen atomor a sulfur atom as a ring constituting and/or may be substituted withan alkyl group having 1 to 6 carbon atoms;

[0010] and Y represents a hydrogen atom, a phenyl group, anacetoxymethyl group, a pivaloyloxymethyl group, an ethoxycarbonyl group,a choline group, a dimethylaminoethyl group, a 5-indanyl group, aphthalidinyl group, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms,an alkoxymethyl group having 2 to 7 carbon atoms, or a phenylalkyl grouphaving 1 to 6 carbon atoms in the alkyl moiety thereof;

[0011] and the two substituents on the cyclopropane ring,

[0012] are in a cis-configuration.

[0013] The present invention also relates to:

[0014] a compound of formula (I), wherein Q is a partial structurerepresented by formula:

[0015] wherein R³, R⁴, R⁵, X¹, X², and Y are as defined above, or a saltor hydrate thereof or a hydrate of the salt;

[0016] a compound of formula (I), wherein Q is a6-carboxy-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazin-10-ylgroup of formula:

[0017] or a salt or hydrate thereof or a hydrate of the salt;

[0018] a compound of formula (I), wherein Q is a8-amino-6-carboxy-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazin-10-ylgroup of formula:

[0019] or a salt or hydrate thereof or a hydrate of the salt;

[0020] a compound of formula (I), wherein Q is a5-amino-3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxyl-4-oxoquinolin-7-ylgroup of formula:

[0021] or a salt or hydrate thereof or a hydrate of the salt;

[0022] a compound of formula (I), wherein Q is a5-amino-3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinolin-7-ylgroup of formula:

[0023] or a salt or hydrate thereof or a hydrate of the salt;

[0024] a compound of formula (I), wherein Q is a3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxyl-4-oxoquinolin-7-ylgroup of formula:

[0025] or a salt or hydrate thereof or a hydrate of the salt;

[0026] a compound of formula (I), wherein n is 2, or a salt or hydratethereof or a hydrate of the salt;

[0027] a compound of formula (I), wherein R¹ and R² are each a hydrogenatom, or a salt or hydrate thereof or a hydrate of the salt;

[0028] a compound of formula (I), wherein R³ is a halogenocyclopropylgroup, or a salt or hydrate thereof or a hydrate of the salt;

[0029] a compound of formula (I), wherein R³ is a1,2-cis-2-halogenocyclopropyl group, or a salt or hydrate thereof or ahydrate of the salt;

[0030] a compound of formula (I), wherein R³ is a stereochemically puresubstituent, or a salt or hydrate thereof or a hydrate of the salt;

[0031] a compound of formula (I), wherein R³ is a(1R,2S)-2-halogenocyclopropyl group, or a salt or hydrate thereof or ahydrate of the salt;

[0032] a compound of formula (I), wherein R³ is a(1R,2S)-2-fluorocyclopropyl group, or a salt or hydrate thereof or ahydrate of the salt;

[0033] a compound of formula (I), wherein X¹ is a halogen atom, or asalt or hydrate thereof or a hydrate of the salt;

[0034] a compound of formula (I), wherein X¹ is a fluorine atom, or asalt or hydrate thereof or a hydrate of the salt;

[0035] a compound of formula (I) which is a stereochemically purecompound, or a salt or hydrate thereof or a hydrate of the salt;

[0036]5-amino-7-{3-[(1S,2S)-2-aminocyclopropyl]-1-pyrrolidinyl}-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid or a salt or hydrate thereof or a hydrate of the salt;

[0037] a drug containing any of the above-described compounds, hydratesthereof, salts thereof, and hydrates of the salts as an activeingredient; and

[0038] an antimicrobial agent containing any of the above-describedcompounds, hydrates thereof, salts thereof, and hydrates of the salts asan active ingredient.

[0039] The present invention also relates to a compound represented byformula (VI) shown below, a salt or hydrate thereof, and a hydrate ofthe salt:

[0040] wherein R¹ and R² each independently represents a hydrogen atomor an alkyl group having 1 to 6 carbon atoms which may be substitutedwith one or more substituents selected from the group consisting of ahydroxyl group, a halogen atom, an alkylthio group having 1 to 6 carbonatoms, and an alkyloxy group having 1 to 6 carbon atoms; one of R¹ andR² may be a protective group for amino group; n represents an integer of1 to 3; Q′ represents a hydrogen atom or a protective group for aminogroup; and the two substituents on the cyclopropane ring,

[0041] are in a cis-configuration;

[0042] a compound of formula (VI), wherein the protective group foramino group is selected from the group consisting of a substituted orunsubstituted alkoxycarbonyl group, a substituted or unsubstitutedaralkyloxycarbonyl group, a substituted or unsubstituted acyl group, asubstituted or unsubstituted alkyl group, a substituted or unsubstitutedaralkyl group, and a substituted silyl group, or a salt or hydratethereof or a hydrate of the salt;

[0043] a compound of formula (VI), wherein the protective group foramino group is selected from the group consisting of a t-butoxycarbonylgroup, a 2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group,a p-methoxylbenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group,an acetyl group, a methoxylacetyl group, a trifluoroacetyl group, achloroacetyl group, a pivaloyl group, a formyl group, a benzoyl group, at-butyl group, a benzyl group, a p-nitrobenzyl group, a p-methoxybenzylgroup, a triphenylmethyl group, a methoxymethyl group, a t-butoxymethylgroup, a tetrahydropyranyl group, a 2,2,2-trichloroethoxymethyl group, atrimethylsilyl group, an isopropyldimethylsilyl group, at-butyldimethylsilyl group, a tribenzylsilyl group, and at-butyldiphenylsilyl group, or a salt or hydrate thereof or a hydrate ofthe salt;

[0044] a compound of formula (VI), wherein Q′ and one of R¹ and R² aredifferent protective groups for amino group, or a salt or hydratethereof or a hydrate of the salt;

[0045] a compound of formula (VI) which is a stereochemically purecompound, or a salt or hydrate thereof or a hydrate of the salt;

[0046] and1-benzyloxycarbonyl-3-[(1S,2S)-2-t-butoxycarbonylaminocyclopropyl]pyrrolidineor a salt or hydrate thereof or a hydrate of the salt.

[0047] The compound according to the present invention, represented byformula (I):

[0048] namely, formula:

[0049] is described with reference to the substituents thereof.

[0050] Substituents R¹ and R² each independently represents a hydrogenatom or an alkyl group having 1 to 6 carbon atoms which may besubstituted with one or more substituents selected from the groupconsisting of a hydroxyl group, a halogen atom, an alkylthio grouphaving 1 to 6 carbon atoms, and an alkyloxy group having 1 to 6 carbonatoms.

[0051] The alkyl group may be a straight-chain or branched having 1 to 6carbon atoms and preferably is a methyl group, an ethyl group, ann-propyl group, and an isopropyl group. The hydroxyl-substituted alkylgroup having 1 to 6 carbon atoms may be a straight-chain or branched andpreferably are a hydroxyethyl group and a hydroxypropyl group.

[0052] The alkylthio group having 1 to 6 carbon atoms preferablyincludes a methylthio group and an ethylthio group. The alkyloxy grouphaving 1 to 6 carbon atoms preferably are a methoxyll group and anethoxyl group.

[0053] Substituent R³ represents an alkyl group having 1 to 6 carbonatoms, an alkenyl group having 2 to 6 carbon atoms, a halogenoalkylgroup having 1 to 6 carbon atoms, a substituted or unsubstitutedcycloalkyl group having 3 to 6 carbon atoms, a substituted orunsubstituted aryl group, a substituted or unsubstituted heteroarylgroup, an alkoxyl group having 1 to 6 carbon atoms, or an alkylaminogroup having 1 to 6 carbon atoms.

[0054] The alkyl group having 1 to 6 carbon atoms preferably are anethyl group. The alkenyl group having 2 to 6 carbon atoms preferably area vinyl group or a 1-isopropenyl group. The halogenoalkyl group having 1to 6 carbon atoms preferably are a 2-fluoroethyl group. The cycloalkylgroup preferably is a cyclopropyl group. The substituent for thecycloalkyl group preferably is a halogen atom, particularly a fluorineatom.

[0055] The aryl group which may have a substituent includes a phenylgroup and a phenyl group having 1 to 3 substituents selected from thegroup consisting of a halogen atom (e.g., fluorine, chlorine, andbromine), a lower alkyl group having 1 to 6 carbon atoms, a hydroxylgroup, an amino group, a nitro group, a lower alkoxyl group having 1 to6 carbon atoms, etc., and preferably are a phenyl group, a2-fluorophenyl group, a 4-fluorophenyl group, 2,4-difluorophenyl group,and a 2-fluoro-4-hydroxyphenyl group.

[0056] The heteroaryl group is a substituent derived from an aromaticheterocyclic compound containing at least one hetero atom selected froma nitrogen atom, an oxygen atom and a sulfur atom and includes a pyridylgroup and a pyrimidyl group. The substituents on the heteroaryl grouppreferably are an alkyl group and a halogen atom.

[0057] The alkoxyl group having 1 to 6 carbon atoms preferably are amethoxyl group. The alkylamino group having 1 to 6 carbon atomspreferably are a methylamino group.

[0058] Substituent R³ is preferably a cycloalkyl group or ahalogenocycloalkyl group, still preferably a cyclopropyl group or a2-halogenocyclopropyl group, in which the halogen atom is preferably afluorine atom.

[0059] Substituent R⁴ represents a hydrogen atom or an alkylthio grouphaving 1 to 6 carbon atoms, or R³ and R⁴ may be taken together with partof the mother skeleton (that is, so as to the nitrogen atom to which R³is bonded and the carbon atom to which R⁴ is bonded to are involved) toform a cyclic structure. The ring formed may contain a sulfur atom as aring constituting atom. It may be substituted with an alkyl group having1 to 6 carbon atoms. The ring can be a 4- to 6-membered ring and may besaturated, partially saturated or unsaturated. The alkylthio grouphaving 1 to 6 carbon atoms preferably are a methylthio group and anethylthio group.

[0060] The condensed ring structure thus formed includes the followingstructures.

[0061] X¹ represents a halogen atom or a hydrogen atom.

[0062] As for the halogen atom, a fluorine atom is preferable. X¹preferably is a fluorine atom or a hydrogen atom.

[0063] Where A is a partial structure of formula (II):

[0064] X² represents a hydrogen atom, an amino group, a halogen atom, acyano group, a halogenomethyl group, a halogenomethoxyl group, an alkylgroup having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbonatoms, an alkynyl group having 2 to 6 carbon atoms, or an alkoxyl grouphaving 1 to 6 carbon atoms. The amino group may have one or moresubstituents selected from the group consisting of a formyl group, analkyl group having 1 to 6 carbon atoms and an acyl group having 2 to 5carbon atoms.

[0065] The alkyl group may be a straight-chain or branched having 1 to 6carbon atoms and preferably are a methyl group, an ethyl group, ann-propyl group, and an isopropyl group. The alkenyl group may be astraight-chain or branched having 2 to 6 carbon atoms and preferably isa vinyl group. The alkynyl group may be a straight-chain or branchedhaving 2 to 6 carbon atoms and preferably is an ethynyl group. Thehalogenomethyl group may contain 1 to 3 halogen atoms, and the halogenatom thereof is preferably a fluorine atom. The alkoxyl group may bethose having 1 to 6 carbon atoms and preferably is a methoxyl group. Thehalogenomethoxyl group may have 1 to 3 halogen atoms, and the halogenatom thereof is preferably a fluorine atom.

[0066] R³ and X² may be taken together with part of the mother skeleton(that is, so as to the nitrogen atom to which R³ is bonded and thecarbon atom to which X² is bonded are involved) to form a cyclicstructure that may contain an oxygen atom, a nitrogen atom or a sulfuratom as a ring constituting atom and/or may be substituted with an alkylgroup having 1 to 6 carbon atoms. The cyclic structure can be a 4- to7-membered ring and may be saturated, partially saturated orunsaturated.

[0067] The condensed ring structure thus formed includes the followingstructures.

[0068] A6-carboxy-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazin-10-ylgroup is particularly preferred of them.

[0069] Substituent R⁵ represents a hydrogen atom, an amino group, ahydroxyl group, a thiol group, a halogenomethyl group, an alkyl grouphaving 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms,an alkynyl group having 2 to 6 carbon atoms or an alkoxyl group having 1to 6 carbon atoms, in which the amino group may be substituted with oneor more substituents selected from the group consisting of a formylgroup, an alkyl group having 1 to 6 carbon atoms, and an acyl grouphaving 2 to 5 carbon atoms.

[0070] The alkyl group can be a straight-chain or branched having 1 to 6carbon atoms and preferably is a methyl group, an ethyl group, ann-propyl group, and an isopropyl group. The alkenyl group can be astraight-chain or branched having 2 to 6 carbon atoms and preferably isa vinyl group. The alkynyl group may be a straight-chain or branchedhaving 2 to 6 carbon atoms and preferably is an ethynyl group. Thehalogenomethyl group may contain 1 to 3 halogen atoms, and the halogenatom thereof preferably is a fluorine atom. The alkoxyl group can bethose having 1 to 6 carbon atoms and preferably is a methoxyl group.

[0071] The acyl group having 2 to 5 carbon atoms which may be asubstitutent for the amino group preferably are an acetyl group, apropanoly group and a butanoyl group.

[0072] Where X² or R⁵ is an amino group, a hydroxyl group or a thiolgroup, these groups may be protected by commonly used protective groups,such as a substituted or unsubstituted alkoxycarbonyl group, asubstituted or unsubstituted aralkyloxycarbonyl group, a substituted orunsubstituted acyl group, a substituted or unsubstituted alkyl group, asubstituted or unsubstituted aralkyl group, and a silyl groupsubstituted with an alkyl group or an aralkyl group (they may be thesame or different).

[0073] Specific examples of the protective group include substituted orunsubstituted alkoxycarbonyl groups, e.g., a t-butoxycarbonyl group anda 2,2,2-trichloroethoxycarbonyl group; substituted or unsubstitutedaralkyloxycarbonyl groups, e.g., a benzyloxycarbonyl group, ap-methoxybenzyloxycarbonyl group, and a p-nitrobenzyloxycarbonyl group;substituted or unsubstituted acyl groups, e.g., an acetyl group, amethoxyacetyl group, a trifluoroacetyl group, a chloroacetyl group, apivaloyl group, a formyl group, and a benzoyl group; substituted orunsubstituted alkyl or aralkyl groups, e.g., a t-butyl group, a benzylgroup, a p-nitrobenzyl group, a p-methoxybenzyl group, a triphenylmethylgroup, and a phenethyl group; ether groups, e.g, a methoxymethyl group,a t-butoxymethyl group, a tetrahydropyranyl group, and a2,2,2-trichloroethoxymethyl group; and substituted silyl groups, e.g., atrimethylsilyl group, an isopropyldimethylsilyl group, at-butyldimethylsilyl group, a tribenzylsilyl group, and at-butyldiphenylsilyl group. The compounds whose substituents areprotected by these protective groups are particularly useful as anintermediate for preparing the compounds of formula (I).

[0074] Y represents a hydrogen atom, a phenyl group, an acetoxymethylgroup, a pivaloyloxymethyl group, an ethoxycarbonyl group, a cholinegroup, a dimethylaminoethyl group, a 5-indanyl group, a phthalidinylgroup, a 5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a3-acetoxy-2-oxobutyl group, an alkyl group having 1 to 6 carbon atoms,an alkoxymethyl group having 2 to 7 carbon atoms, or a phenylalkyl grouphaving 1 to 6 carbon atoms in the alkyl moiety thereof.

[0075] The alkyl group having 1 to 6 carbon atoms preferably are amethyl group, an ethyl group, a propyl group, an isopropyl group, abutyl group and a t-butyl group. The alkoxymethyl group having 2 to 7carbon atoms preferably are a methoxymethyl group and an ethoxymethyl.The phenylalkyl group having 1 to 6 carbon atoms in the alkyl moietythereof preferably are a benzyl group and a phenetyl group.

[0076] Where A is a partial structure represented by formula (II), apreferable combination of substituents R⁵ and X² is that R⁵ is selectedfrom an amino group, a hydrogen atom, a hydroxyl group, and an alkylgroup having 1 to 6 carbon atoms, and X² is selected from an alkyl grouphaving 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms,a halogenomethoxyl group, and a hydrogen atom. In a still preferredcombination, R⁵ is an amino group, a hydrogen atom, a hydroxyl group ora methyl group, and X² is a methyl group, a methoxyl group, adifluoromethoxyl group or a hydrogen atom.

[0077] In the above case, X¹ preferably is a fluorine atom with respectto R⁵ and X². Where X¹ and X² are both a halogen atom, X¹ preferably isa fluorine atom, and X² preferably is a fluorine atom or a chlorineatom.

[0078] The compounds according to the present invention arecharacterized in that the quinolone skeleton has a substituentrepresented by formula:

[0079] at the 7-position or a corresponding position, namely, theformula that the amino group or alkylamino group:

[0080] and a 4-membered (n=1) to 6-membered (n=3) nitrogen-containingsaturated heterocyclic substituent:

[0081] are bonded to the cyclopropyl group.

[0082] While the amino moiety and the nitrogen-containing saturatedheterocyclic moiety can be in a cis- or trans-configuration with respectto the cyclopropyl group (cyclopropane ring), a cis-configuration shownbelow is preferred.

[0083] Where n is 2 or 3, the nitrogen-containing saturated heterocyclicmoiety and the cyclopropane ring are bonded in two modes to provideisomers. Such isomers are illustrated below, taking the structurewherein n=2 for instance. Similar isomers are produced when n is 3. Thepresent invention is intended to embrace all these isomers under thescope thereof.

[0084] The cyclopropyl moiety may have further substituents, forexample, a fluorine atom, a methyl group, an ethyl group, atrifluoromethyl group, etc.

[0085] The halogenocyclopropyl group as R³ is then described. Thesubstituent halogen atom includes a fluorine atom and a chlorine atom,with a fluorine atom being preferred.

[0086] It is particularly preferred that the substituent halogen atomand the pyridonecarboxylic acid moiety be in a cis-configuration withrespect to the cyclopropane ring.

[0087] Regardless of stereoisomerism of the 7-positioned substituent,the cis-2-halogenocyclopropyl moiety of R³ makes a pair of antipodes,each of which was observed to exhibit potent antimicrobial activity andhigh safety.

[0088] Where the compound of formula (I) has such a structure thatproduces diastereomers, it is desirable to administer a compoundcomprising a pure diastereomer in administration to humans or animals.The language “a compound comprising a pure diastereomer” as used hereinis construed as including not only a compound containing no otherdiastereomer at all but a compound containing other diastereomers tosuch an extent that the compound is recognized to be stereochemicallypure as a whole. In other words, it is construed as meaning that otherdiastereomers may exist to some extent as long as the existence gives nosubstantial influence on physiological activities or physicochemicalconstants.

[0089] The language “stereochemically pure” as used herein is intendedto mean that a compound comprises only one of its stereoisomers ascribedto its asymmetric carbon atom. The latitude of the term “pure” in “purediastereomer” also applies here.

[0090] The pyridonecarboxylic acid derivative of the present inventionmay present in either a free form or a form of an acid addition salt ora carboxylic acid salt. Acid addition salts include inorganic acidsalts, such as a hydrochloride, a sulfate, a nitrate, a hydrobromide, ahydroiodide, and a phosphate; and organic acid salts, such as anacetate, a metanesulfonate, a benzenesulfonate, a toluenesulfonate, acitrate, a maleate, a fumarate, and a lactate.

[0091] The carboxylic acid salts include inorganic salts and organicsalts, such as alkali metal salts, e.g., a lithium salt, a sodium salt,and a potassium salt; alkaline earth metal salts, e.g., a magnesium saltand a calcium salt; an ammonium salt; a triethylamine salt, anN-methylglucamine salt, and a tris-(hydroxymethyl)aminomethane salt.

[0092] The free pyridonecarboxylic acid derivatives, acid addition saltsthereof, and carboxylic acid salts thereof may be present as a hydrate.

[0093] On the other hand, quinolone derivatives with the carboxylic acidmoiety thereof having an ester form are useful as an intermediate forsynthesis or a pro-drug. For example, alkyl esters, benzyl esters,alkoxylalkyl esters, phenylalkyl esters, and phenyl esters are useful assynthetic intermediates.

[0094] Esters which can be used as pro-drugs are those which aresusceptible to an in vivo cleavage to form a free carboxylic acid,including an acetoxymethyl ester, a pivaloyloxymethyl ester, anethoxycarbonyl ester, a choline ester, a dimethylaminoethyl ester, a5-indanyl ester, a phthalidinyl ester, a5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl ester, and oxoalkyl esters, such asa 3-acetoxy-2-oxobutyl ester.

[0095] The compound of formula (I) can be prepared through variousprocesses. A preferred process comprises reacting a compound representedby formula (III):

[0096] wherein X³ represents a leaving group, such as a fluorine atom, achlorine atom, a bromine atom, an alkylsulfonyl group having 1 to 3carbon atoms, or an arylsulfonyl group, e.g., a benzenesulfonyl group ora toluenesulfonyl group; Y has the same meaning as in formula (I) orrepresents a boron-containing group represented by formula (IV):

—B(R⁶)R⁷   (IV)

[0097] wherein R⁶ and R⁷ each represents a fluorine atom or a loweralkylcarbonyloxy group;

[0098] and R³, R⁴, R⁵, X¹, and X² are as defined in formula (I), with acompound represented by formula (V):

[0099] wherein R¹, R², and n are as defined in formula (I), except thatR¹ may be a nitrogen-protective group Rx.

[0100] Any protective group generally used in the art can be used asprotective group Rx. Examples of useful protective groups includealkoxylcarbonyl groups, e.g., a t-butoxycarbonyl group and a2,2,2-trichloroethoxycarbonyl group; aralkyloxycarbonyl groups, e.g., abenzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, and ap-nitrobenzyloxycarbonyl group; acyl groups, e.g., an acetyl group, amethoxyacetyl group, a trifluoroacetyl group, a chloroacetyl group, apivaloyl group, a formyl group, and a benzoyl group; alkyl or aralkylgroups, e.g., a t-butyl group, a benzyl group, a p-nitrobenzyl group, ap-methoxybenzyl group, and a triphenylmethyl group; ether groups, e.g, amethoxymethyl group, a t-butoxymethyl group, a tetrahydropyranyl group,and a 2,2,2-trichloroethoxymethyl group; and substituted silyl groups,e.g., a trimethylsilyl group, an isopropyldimethylsilyl group, at-butyldimethylsilyl group, a tribenzylsilyl group, and at-butyldiphenylsilyl group,

[0101] or an acid addition salt thereof.

[0102] The resulting compound in which Y is an alkyl group having 1 to 6carbon atoms, an alkoxymethyl group having 2 to 7 carbon atoms or aphenylalkyl group having 1 to 6 carbon atoms in the alkyl moiety thereofcan be converted to the corresponding carboxylic acid by hydrolysisunder an acidic or basic condition commonly used for hydrolysis ofcarboxylic acid esters. The protective group, if any, is removed underproperly selected conditions to obtain a desired compound (I).

[0103] The compound obtained by the substitution reaction between thecompound (III) wherein Y is the group (IV) and the compound (V) can beconverted to the corresponding carboxylic acid by treatment with anacidic or basic compound.

[0104] The substitution reaction between the compound of formula (III)and the compound of formula (V) is carried out with or without asolvent. The solvent, if used, is not limited as long as it is inertunder the reaction conditions. Suitable solvents include dimethylsulfoxide, pyridine, acetonitrile, ethanol, chloroform,dimethylformamide, dimethylacetamide, N-methylpyrrolidone,tetrahydrofuran, water, and 3-methoxybutanol. These solvents may be usedas a mixture thereof.

[0105] The reaction is usually performed at room temperature to 200° C.,preferably 25 to 150° C., for 0.5 to 48 hours. The reaction usuallycompletes in about 0.5 to 2 hours. It is advantageous to conduct thereaction in the presence of an acid acceptor, such as an inorganic base(e.g., an alkali metal or alkaline earth metal carbonate orhydrogencarbonate) or an organic base (e.g., triethylamine, pyridine or1,8-diazabicycloundecene).

[0106] The compound of formula (V) can be prepared by various processes.A preferred process is shown in Reference Examples hereinafter given,but the process is not limited thereto. Most generally, the compound offormula (V) is prepared by removing the protective group from a compoundrepresented by formula (VI) shown below, in which the nitrogen atom isprotected by a protective group Q′.

[0107] wherein R¹ and R² each represent a hydrogen atom or an alkylgroup having 1 to 6 carbon atoms, which may have one or moresubstituents selected from the group consisting of a hydroxyl group, ahalogen atom, an alkylthio group having 1 to 6 carbon atoms, and analkyloxy group having 1 to 6 carbon atoms; one of R¹ and R² may be anprotective group for amino group; n represents an integer of 1 to 3; Q′represents a protective group for amino group; and the two substituentson the cyclopropane ring,

[0108] are in a cis-configuration.

[0109] The compound (VI) may exist in the form of a salt, a hydrate, ora hydrate of the salt. Acid addition salts include inorganic acid saltsand organic acid salts. Examples of the inorganic acid salts are ahydrochloride, a sulfate, a nitrate, a hydrobromide, a hydroiodide, anda phosphate. Examples of the organic acid salts include sulfonates, suchas a metanesulfonate, a benzenesulfonate, and a toluenesulfonate, andcarboxylates, such as an acetate, a citrate, a maleate, a fumarate, anda lactate.

[0110] Where Q′ and one of R¹ and R² both represent an protective groupfor amino group, while they may be the same or different, it isadvantageous for the preparation of the compound (I) that theseprotective groups are different so that they are cleaved under therespective different reaction conditions.

[0111] The protective group for amino group as R¹ or R² and Q′ includessubstituted or unsubstituted alkoxycarbonyl groups, e.g., at-butoxycarbonyl group and a 2,2,2-trichloroethoxycarbonyl group;substituted or unsubstituted aralkyloxycarbonyl groups, e.g., abenzyloxycarbonyl group, a p-methoxybenzyloxycarbonyl group, and ap-nitrobenzyloxycarbonyl group; substituted or unsubstituted acylgroups, e.g., an acetyl group, a methoxyacetyl group, a trifluoroacetylgroup, a chloroacetyl group, a pivaloyl group, a formyl group, and abenzoyl group; substituted or unsubstituted alkyl or aralkyl groups,e.g., a t-butyl group, a benzyl group, a p-nitrobenzyl group, ap-methoxybenzyl group, and a triphenylmethyl group; ether groups, e.g, amethoxymethyl group, a t-butoxymethyl group, a tetrahydropyranyl group,and a 2,2,2-trichloroethoxymethyl group; and substituted silyl groups,e.g., a trimethylsilyl group, an isopropyldimethylsilyl group, at-butyldimethylsilyl group, a tribenzylsilyl group, and at-butyldiphenylsilyl group.

[0112] Cis-2-fluorocyclopropylamine comprising a pure isomer, which ispreferred for the synthesis of the compound of formula (I) comprising apure isomer, can be synthesized by, for example, the process describedin JP-A-2-231475 (the term “JP-A” as used herein means an “unexaminedpublished Japanese patent application”). Synthesis of the compound offormula (I) comprising a pure isomer from the resulting optically activecis-2-fluorocyclopropylamine derivative can be carried out by, forexample, the process described in JP-A-2-231475.

[0113] The compounds of the present invention have potent antimicrobialactivity and are therefore useful as drugs for humans, animals orfishes, agricultural chemicals, or food preservatives.

[0114] For use as drugs for humans, the dose of the compound is in therange of from 50 mg to 1 g, and preferably from 100 mg to 300 mg, perday for an adult.

[0115] For veterinary use, the dose is generally in the range of from 1to 200 mg, and preferably from 5 to 100 mg, per kg of body weight perday while varying depending on the purpose of administration (fortherapy or for prevention), the kind and the size of the animal, thekind of the pathogenic organisms, and severity of symptom.

[0116] The above-mentioned daily dose is given once a day or in 2 to 4divided doses. If necessary, a daily dose may exceed the above-specifiedrange.

[0117] The compounds according to the present invention are active on abroad range of microorganisms causing various infectious diseases andeffective to prevent, alleviate or cure diseases caused by thesepathogens.

[0118] Examples of bacteria or bacterium-like microorganisms on whichthe compounds of the invention are effective include staphylococci,Streptococcus pyogenes, Streptococcus haemolyticus, Streptococcusfaecalis, Streptococcus pneumoniae, peptostreptococci, Neisseriagonorrhoeae, Escherichia coli, Citrobacter sp., Shigella sp., Klebsiellapneumoniae, Enterobacter sp., Serratia sp., Proteus sp., Pseudomonasaeruginosa, Haemophilus influenzae, Acinetobacter sp., Campylobactersp., and Chlamydozoon trachomatis.

[0119] Diseases which are caused by these pathogens includefolliculitis, furuncle, carbuncle, erysipelas, phlegmon,lymphangitis/lymphadenitis, felon, subcutaneous abscess, spiradenitis,acne agminata, infectious atheroma, perianal abscess, mastadenitis,superficial secondary infections after trauma, burn or surgery trauma,pharyngolaryngitis, acute bronchitis, tonsillitis, chronic bronchitis,bronchiectasis, diffuse panbronchiolitis, secondary infections ofchronic respiratory diseases, pneumonia, pyelonephritis, cystitis,prostatitis, epididymitis, gonococcal urethritis, non-gonococcalurethritis, cholecystitis, cholangitis, bacillary dysentery, enteritis,adnexitis, intrauterine infections, bartholinitis, blepharitis,hordeolum, dacryocystitis, tarsadenitis, keratohelcosis, otitis media,sinusitis, paradentosis, pericoronitis, gnathitis, peritonitis,endocarditis, septicemia, meningitis, and skin infections.

[0120] The compounds of the present invention are also effective onvarious microorganisms causing veterinary diseases, such as thosebelonging to the genera Escherichia, Salmonella, Pasteurella,Haemophilus, Bordetella, Staphylococcus, and Mycoplasma. Illustrativeexamples of the veterinary diseases include those of fowl, such ascolibacillosis, pullorum disease, avian paratyphosis, fowl cholera,infectious coryza, staphylomycosis, and mycoplasmosis; those of pigs,such as colibacillosis, salmonellosis, pasteurellosis, hemophilusinfections, atrophic rhinitis, exudative epidermitis, and mycoplasmosis;those of cattle, such as colibacillosis, salmonellosis, hemorrhagicsepticemia, mycoplasmosis, bovine contagious pleuropneumonia, and bovinemastitis; those of dogs, such as colisepsis, salmonellosis, hemorrhagicsepticemia, pyometra, and cystitis; those of cats, such as exudativepleurisy, cystitis, chronic rhinitis, and hemophilus infections; andthose of kittens, such as bacterial diarrhea and mycoplasmosis.

[0121] Dosage forms of pharmaceutical preparations containing thecompound of the present invention are appropriately selected accordingto the administration route and can be prepared by conventionalpreparation methods. Examples of dosage forms for oral administrationinclude tablets, powders, granules, capsules, solutions, syrups,elixirs, and oily or aqueous suspensions.

[0122] Injectable preparations may contain adjuvants, such asstabilizers, antiseptics, and solubilizers. The injectable solutionwhich may contain these adjuvants may be put into a container andsolidified by, for example, lyophilization to prepare a solidpreparation which is dissolved on use. The container may contain eithera single dose or multiple doses.

[0123] Preparations for external application include solutions,suspensions, emulsions, ointments, gels, creams, lotions, and sprays.

[0124] Solid preparations may contain, in addition to the activecompound, pharmaceutically acceptable additives. For example, the activecompound is mixed with additives selected according to necessity fromamong fillers, extenders, binders, disintegrators, absorptionaccelerators, wetting agents, and lubricants and formulated into solidpreparations.

[0125] Liquid preparations include solutions, suspensions, andemulsions. They may contain adjuvants, such as suspending agents,emulsifiers, and so forth.

[0126] The compound can be administered to animals orally eitherdirectly or by mixing with feedstuff, or in a dissolved form directlygiven to animals or by mixing with water or feedstuff or non-orally byinjection.

[0127] For veterinary use, the compound can be formulated into powders,fine granules, soluble powders, syrups, solutions, and injectionsaccording to the customary methods in the art.

[0128] Formulation Examples are shown below.

Formulation Example 1 Capsules

[0129] Compound of Example 2 100.0 mg Corn starch  23.0 mg CMC · Ca 22.5 mg Hydroxymethyl cellulose  3.0 mg Magnesium stearate  1.5 mgTotal: 150.0 mg

Formulation Example 2 Solution

[0130] Compound of Example 2 1 to 10 g Acetic acid or sodium hydroxide0.5 to 2 g Ethyl p-hydroxybenzoate 0.1 g Purified water 87.9 to 98.4 gTotal: 100 g

Formulation Example 3 Powder for Mixing with Feed

[0131] Compound of Example 2 1 to 10 g Corn starch 89.5 to 98.5 g Lightanhydrous silicic acid 0.5 g Total: 100 g

BEST MODE OF CARRYING OUT THE INVENTION

[0132] The present invention will further be illustrated in greaterdetail by way of Examples and Reference Examples, but the presentinvention should not be construed as being limited thereto. Theantimicrobial activity of the compounds prepared was examined inaccordance with the standard method specified by the JapanChemotherapeutic Society, and the results obtained were expressed interms of minimum inhibitory concentration (MIC; μg/ml).

EXAMPLE 15-Amino-7-[3-(1,2-cis-2-aminocyclopropyl)-1-pyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicAcid (Isomer A)

[0133] Triethylamine (2.5 ml) was added to a solution of 316.1 mg (1.01mmol) of5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid and 343.6 mg (1.52 mmol) of1-benzyloxycarbonyl-3-(cis-2-t-butoxycarbonylaminocyclopropyl)pyrrolidine(isomer A) in 5 ml of dimethyl sulfoxide, and the mixture was heatedunder reflux at 130° C. for 4 days. The solvent was removed byevaporation under reduced pressure, and chloroform was added to theresidue, followed by washing successively with a 10% citric acid aqueoussolution and a saturated sodium chloride aqueous solution. The organiclayer was dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. To the residue was added 10 ml ofconcentrated hydrochloric acid under cooling with ice. After stirring atroom temperature for 30 minutes, water was added to the reactionmixture, followed by extraction with dichloromethane. The aqueous layerwas neutralized with 5 N and 1N sodium hydroxide aqueous solutions andextracted with chloroform. The organic layer was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was recrystallized from ethanol and diethyl ether to give122.8 mg (29.0%) of the title compound (isomer A) as yellow crystals.

[0134]¹H-NMR (0.1N-NaOD) δ ppm: 0.00-0.10 (1H, m), 0.55-0.75 (2H, m),1.00-1.15 (1H, m), 1.35-1.50 (1H, m), 1.55-1.80 (1H, m), 1.85-2.00 (1H,m), 2.00-2.15 (1H, m), 2.15-2.30 (4H, m), 3.10-3.70 (4H, m), 3.80-3.90(1H, m), 4.60-5.00 (1H, m), and 8.18 and 8.20 (1H, d each, J=2.9, 2.4 Hzeach).

[0135] Elementary Analysis for C₂₁H₂₄F₂N₄O₃: Calcd. (%): C, 60.28; H,5.78; N, 13.39. Found (%): C, 60.09; H, 5.96; N, 13.06

EXAMPLE 25-Amino-7-[3-(1,2-cis-2-aminocyclopropyl)-1-pyrrolidinyl]-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicAcid (Isomer B)

[0136] Triethylamine (2 ml) was added to a solution of 195.9 mg (0.63mmol) of5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid and 213.0 mg (0.94 mmol) of1-benzyloxycarbonyl-3-(cis-2-t-butoxycarbonylaminocyclopropyl)pyrrolidine(isomer B) in 4 ml of dimethyl sulfoxide, and the mixture was heatedunder reflux at 130° C. for 45 hours. The solvent was removed byevaporation under reduced pressure, and chloroform was added to theresidue, followed by washing successively with a 10% citric acid aqueoussolution and a saturated sodium chloride aqueous solution. The organiclayer was dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. To the residue was added 10 ml ofconcentrated hydrochloric acid under cooling with ice. After stirring atroom temperature for 30 minutes, water was added to the reactionmixture, followed by extraction with dichloromethane. The aqueous layerwas neutralized with 5N and 1N sodium hydroxide aqueous solutions andextracted with chloroform. The aqueous layer was adjusted to a pH of 10or higher with a 5N sodium hydroxide aqueous solution and extracted withchloroform. The aqueous layer was neutralized with concentratedhydrochloric acid and 1N hydrochloric acid and extracted withchloroform. The organic layer was dried over anhydrous sodium sulfate,and the solvent was evaporated under reduced pressure. The residue wasrecrystallized from ethanol and diethyl ether to give 65.9 mg (25.1%) ofthe title compound (isomer B) as yellow crystals.

[0137]¹H-NMR (0.1N-NaOD) δ ppm: 0.00-0.10 (1H, m), 0.55-0.70 (2H, m),0.95-1.15 (1H, m), 1.30-1.50 (1H, m), 1.60-1.80 (1H, m), 1.80-2.10 (2H,m), 2.10-2.25 (4H, m), 3.00-3.70 (4H, m), 3.75-3.85 (1H, m), 4.65-4.95(1H, m), and 8.13 and 8.14 (1H, d each, J=2.9, 2.0 Hz each).

[0138] Elementary Analysis for C₂₁H₂₄F₂N₄O₃.0.5H₂O: Calcd. (%): C,59.01; H, 5.90; N, 13.11. Found (%): C, 59.10; H, 5.66; N, 13.06

EXAMPLE 35-Amino-7-{3-[(1S,2S)-2-aminocyclopropyl]-1-pyrrolidinyl}-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicAcid (Isomer B¹)

[0139] Triethylamine (4 ml) was added to a solution of 526.3 mg (1.69mmol) of5-amino-6,7-difluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid and 572.2 mg (2.53 mmol) of1-benzyloxycarbonyl-3-[(1S,2S)-2-t-butoxycarbonylaminocyclopropyl]pyrrolidine(isomer B) in 8 ml of dimethyl sulfoxide, and the mixture was heatedunder reflux at 130° C. for 90 hours. The solvent was removed byevaporation under reduced pressure, and chloroform was added to theresidue, followed by washing with a 10% citric acid aqueous solution anda saturated sodium chloride aqueous solution. The organic layer wasdried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure. The residue was purified by silica gel columnchromatography (chloroform:methanol=9:1) to obtain 551.4 mg of aprotected compound and 141.4 mg of a mixture of the protected compoundand by-products as a brown caramel-like substance.

[0140] To the resulting protected compound (551.4 mg) was added 10 ml ofconcentrated hydrochloric acid under ice-cooling, followed by stirringat room temperature for 20 minutes. Water was added to the reactionmixture, and the mixture was extracted with dichloromethane. The aqueouslayer was neutralized with 5N and 1N sodium hydroxide aqueous solutionsand extracted with chloroform. The organic layer was removed byevaporation, and the residue was adjusted to a pH of 10 or higher withwater and a 1N sodium hydroxide aqueous solution and extracted withchloroform. The aqueous layer was neutralized with concentratedhydrochloric acid and 1N hydrochloric acid and extracted withchloroform. The first aqueous layer was adjusted to a pH of 10 or higherwith a 5N sodium hydroxide aqueous solution and extracted withchloroform. The aqueous layer was neutralized with concentratedhydrochloric acid and 1N hydrochloric acid and extracted withchloroform. The combined organic layer was dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure to obtain286.1 mg of a crude carboxylic acid.

[0141] The mixture (141.4 mg) of the protected compound and by-productswas similarly treated to obtain 62.3 mg of a crude carboxylic acid.

[0142] Recrystallization of the resulting crude carboxylic acid fromethanol gave 204.4 mg (29.0%) of the title compound as yellow crystals.

[0143]¹H-NMR (0.1N-NaOD) δ ppm: −0.05-0.05 (1H, m), 0.55-0.65 (2H, m),0.90-1.10 (1H, m), 1.30-1.40 (1H, m), 1.60-1.70 (1H, m), 1.80-1.90 (1H,m), 2.00-2.10 (1H, m), 2.10-2.20 (4H, m), 3.20-3.30 (1H, m), 3.30-3.40(2H, m), 3.50-3.60 (1H, m), 3.70-3.80 (1H, m), 4.70-4.95 (1H, m), and8.11 (1H, brs).

[0144] Elementary Analysis for C₂₁H₂₄F₂N₄O₃: Calcd. (%): C, 60.28; H,5.78; N, 13.39. Found (%): C, 60.21; H, 5.72; N, 13.15

[0145] Melting Point: 193-196° C.

REFERENCE EXAMPLE A Cis-2-methoxycarbonylcyclopropanecarboxylic Acid

[0146] To 150 ml of a methanol solution of 14.68 g (92.8 mmol) ofdimethyl cis-1,2-cyclopropanedicarboxylate was added 67 ml of an aqueoussolution of 7.52 g (113.9 mmol) of potassium hydroxide under coolingwith ice, and the mixture was stirred at room temperature for 24 hours.After completion of the reaction, the solvent was removed by evaporationunder reduced pressure, and to the residue was added water. The reactionmixture was washed with diethyl ether. The aqueous layer was adjusted topH 2 with concentrated hydrochloric acid and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure to give 12.38 g(92.5%) of the title compound as a colorless oily substance.

[0147]¹H-NMR (CDCl₃) δ ppm: 1.35 (1H, dt, J=8.3, 4.9 Hz), 1.70 (1H, dt,J=6.8, 4.9 Hz), 2.05-2.20 (2H, m), and 3.72 (3H, m).

REFERENCE EXAMPLE B t-Butyl Cis-2-methoxycarbonylcyclopropanecarboxylate

[0148] To 70 ml of an anhydrous tetrahydrofuran solution of 6.83 g (47.4mmol) of cis-2-methoxycarbonylcyclopropanecarboxylic acid were added1.16 g (9.48 mmol) of dimethylaminopyridine and 13.45 g (61.6 mmol) ofdi-t-butyl dicarbonate at room temperature, and the mixture was stirredat the same temperature for 4 hours. After completion of the reaction,the solvent was removed by evaporation under reduced pressure, and ethylacetate was added to the residue. The mixture was washed successivelywith 0.5N hydrochloric acid, water, and a saturated sodium chlorideaqueous solution. The organic layer was dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure to give9.49 g (quantitative) of the title compound as a brown oily substance.

[0149]¹H-NMR (CDCl₃) δ ppm: 1.10-1.20 (1H, m), 1.44 (9H, s), 1.55-1.65(1H, m), 1.95-2.05 (2H, m), and 3.67 (3H, s).

REFERENCE EXAMPLE C Cis-2-t-butoxycarbonylcyclopropanecarboxylic Acid

[0150] To 100 ml of a methanol solution of 9.49 g (47.4 mmol) of t-butylcis-2-methoxycarbonylcyclopropanecarboxylate was added 40 ml of anaqueous solution of 4.06 g (61.5 mmol) of potassium hydroxide undercooling with ice, followed by stirring at room temperature for 24 hours.After completion of the reaction, the solvent was evaporated underreduced pressure. Water was added to the residue, and the mixture waswashed with diethyl ether. The aqueous layer was adjusted to a pH of 2to 3 with concentrated hydrochloric acid and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure to give 7.56 g (85.7%)of the title compound as a pale yellow solid.

[0151]¹H-NMR (CDCl₃) δ ppm: 1.30-1.40 (1H, m), 1.45 (9H, s), 1.60-1.65(1H, m), and 2.00-2.10 (2H, m)

REFERENCE EXAMPLE D Ethyl3-(Cis-2-t-butoxycarbonylcyclopropyl)-3-oxopropionate

[0152] To 100 ml of an anhydrous tetrahydrofuran solution of 7.56 g(40.6 mmol) of cis-2-t-butoxycarbonylcyclopropanecarboxylic acid wasadded 7.57 g (46.7 mmol) of 1,1-carbonyldiimidazole under cooling withice. After stirring the mixture was stirred at room temperature for 2hours, the solvent was evaporated under reduced pressure. To 50 ml of ananhydrous tetrahydrofuran solution of the resulting residue was added 80ml of an anhydrous tetrahydrofuran solution of 101.5 mmol of previouslyprepared magnesium monoethyl malonate was added, followed by stirringovernight. After completion of the reaction, the solvent was removed byevaporation under reduced pressure, and ethyl acetate was added to theresidue. The mixture was washed successively with 0.5N hydrochloricacid, a saturated sodium hydrogencarbonate aqueous solution, and asaturated sodium chloride aqueous solution. The organic layer was driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=7:3) to give 6.67 g (64.1%) of thetitled compound as a yellow oily substance.

[0153]¹H-NMR (CDCl₃) δ ppm: 1.20 (1H, dt, J=7.8, 4.9 Hz), 1.29 (3H, t,J=7.3 Hz), 1.42 (9H, s), 1.71 (1H, dt, J=6.8, 4.9 Hz), 2.00-2.10 (1H,m), 2.30-2.40 (1H, m), 3.55 (1H, d, J=15.6 Hz), 3.57 (1H, d, J=15.6 Hz),4.20 (2H, q, J=7.3 Hz).

REFERENCE EXAMPLE E Ethyl 3-(Cis-2-t-butoxycarbonylcyclopropyl)acrylate

[0154] To 70 ml of a methanol solution of 6.67 g (26.0 mmol) of ethyl3-(cis-2-t-butoxycarbonylcyclopropyl)-3-oxopropionate was added 492.2 mg(13.0 mmol) of sodium borohydride at −10° C., and the mixture wasstirred at that temperature for 20 minutes. A saturated ammoniumchloride aqueous solution was added thereto, and the reaction mixturewas extracted with chloroform. The organic layer was dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure to obtain 6.52 g (97.0%) of a crude alcohol as a colorless oilysubstance.

[0155] To 150 ml of a dichloromethane solution of the crude alcohol(6.52 g, 25.2 mmol) were added 7.04 ml (50.4 mmol) of triethylamine and2.54 ml (32.8 mmol) of methanesulfonyl chloride while cooling with ice.After the mixture was stirred at the same temperature for 1.5 hours,8.30 ml (55.4 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was addedthereto, followed by stirring at room temperature for 18 hours. Thesolvent was evaporated under reduced pressure, and chloroform was addedto the residue. The mixture was washed successively with 0.1Nhydrochloric acid and a saturated sodium chloride aqueous solution. Theorganic layer was dried over anhydrous sodium sulfate, and the solventwas removed by evaporation under reduced pressure to give 6.07 g(quantitative) of the title compound as a yellow oily substance.

[0156]¹H-NMR (CDCl₃) δ ppm: 1.27 (3H, t, J=7.3 Hz), 1.25-1.35 (1H, m),1.35-1.45 (1H, m), 1.46 (9H, s), 1.90-2.05 (2H, m), 4.10-4.20 (2H, m),6.00 (1H, d, J=15.6 Hz), and 6.90 (1H, ddd, J=15.6, 8.8, 1.5 Hz).

REFERENCE EXAMPLE F Ethyl3-(Cis-2-t-butoxycarbonylcyclopropyl)-3-nitroethylpropionate

[0157] To 60 ml of a nitromethane solution of 6.07 g (25.2 mmol) ofethyl 3-(cis-2-t-butoxycarbonylcyclopropyl)acrylate was added 3.48 ml(27.7 mmol) of tetramethylguanidine at room temperature, and the mixturewas stirred for 6 hours. To the reaction mixture was further added 0.32ml (2.52 mmol) of tetramethylguanidine, followed by stirring for 18hours. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography (hexane:ethylacetate=85:15) to give 6.536 g (85.9%) of the title compound as a paleyellow oily substance.

[0158]¹H-NMR (CDCl₃) δ ppm: 0.95-1.10 (2H, m), 1.20-1.30 (4H, m), 1.46and 1.48 (9H, s each), 1.65-1.80 (1H, m), 2.40-2.70 (2H, m), 2.70-2.80(1H, m), 4.10-4.20 (2H, m), and 4.45-4.55 and 4.60-4.75 (2H, m each)

REFERENCE EXAMPLE G3-(Cis-2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one

[0159] To 200 ml of a methanol solution of 6.536 g (21.7 mmol) of ethyl3-(cis-2-t-butoxycarbonylcyclopropyl)-3-nitroethylpropionate were added5 g of 10% palladium-on-carbon and 13.68 g (217 mmol) of ammoniumformate at room temperature, and the mixture was stirred at the sametemperature for 1.5 hours. After completion of the reaction, the solventwas evaporated under reduced pressure. Water was added to the residue,and the mixture was extracted with chloroform. The organic layer wasdried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure to give a crude amine.

[0160] A toluene solution (150 ml) of the resulting crude amine washeated at 110 to 120° C. for 2 hours. The solvent was evaporated underreduced pressure to give 4.89 g (quantitative) of the title compound asyellow crystals.

[0161]¹H-NMR (CDCl₃) δ ppm: 0.90-1.10 (2H, m), 1.20-1.35 (1H, m), 1.45(9H, s), 1.65-1.75 (1H, m), 2.10-2.70 (3H, m), 3.10-3.20 and 3.20-3.30(1H, m each), 3.35-3.45 and 3.55-3.65 (1H, m each), and 6.06 (1H, brs).

REFERENCE EXAMPLE H1-Benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one

[0162] To 30 ml of a dimethylformamide solution of 2.288 g (10.2 mmol)of 3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one was added 406.2mg (10.2 mmol) of sodium hydride under cooling with ice, followed bystirring at room temperature for 1.5 hours. Then, 1.81 ml (15.3 mmol) ofbenzyl chloride was added thereto dropwise, followed by stirring for 2.5hours. After completion of the reaction, water was added to the reactionmixture, and the mixture was extracted with ethyl acetate, and theorganic layer was washed with water and a saturated sodium chlorideaqueous solution. The organic layer was dried over anhydrous sodiumsulfate, and the solvent was removed by evaporation under reducedpressure. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=7:3) to give 1.121 g (35.0%) of1-benzyl-3-(2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one (isomer A: anisomer attributed to the steric configuration of the cyclopropyl groupbonded to the carbon atom of the pyrrolidine ring) as a colorless solid.The column was then eluted with hexane:ethyl acetate=1:1 to give 670.9mg (20.9%) of1-benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one (isomerB: an isomer attributed to the steric configuration of the cyclopropylgroup bonded to the carbon atom of the pyrrolidine ring) as a colorlesssolid.

[0163] Isomer A:

[0164]¹H-NMR (CDCl₃) δ ppm: 0.85-1.00 (2H, m), 1.10-1.25 (1H, m), 1.45(9H, s), 1.65-1.75 (1H, m), 2.25 (1H, dd, J=16.1, 6.4 Hz), 2.35-2.45(1H, m), 2.50 (1H, dd, J=16.1, 8.8 Hz), 3.08 (1H, dd, J=9.8, 5.9 Hz),3.43 (1H, t, J=8.8 Hz), 4.45 (1H, d, J=14.7 Hz), 4.46 (1H, d, J=14.7Hz), and 7.20-7.40 (5H, m).

[0165] Isomer B:

[0166]¹H-NMR (CDCl₃) δ ppm: 0.90-1.00 (1H, m), 1.00-1.10 (1H, m),1.15-1.25 (1H, m), 1.37 (9H, s), 1.55-1.65 (1H, m), 2.33 (1H, dd,J=16.1, 7.3 Hz), 2.35-2.45 (1H, m), 2.68 (1H, dd, J=16.1, 8.3 Hz), 2.99(1H, dd, J=9.3, 5.9 Hz), 3.20 (1H, dd, J=9.3, 7.8 Hz), 4.39 (1H, d,J=14.7 Hz), 4.48 (1H, d, J=14.7 Hz), and 7.20-7.40 (5H, m).

REFERENCE EXAMPLE I1-Benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine-2-thione(Isomer A)

[0167] To 40 ml of a toluene solution of 1.990 g (6.31 mmol) of1-benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one (isomerA) was added 1.378 g (3.41 mmol) of a Lawson's reagent, and the mixturewas stirred at 50 to 60° C. for 1.5 hours. After completion of thereaction, the reaction mixture was subjected to silica gel columnchromatography (hexane:ethyl acetate=7:3) to give 1.707 g (81.6%) of thetitle compound (isomer A) as a pale yellow solid.

[0168]¹H-NMR (CDCl₃) δ ppm: 0.80-0.90 (1H, m), 0.90-1.00 (1H, m),1.10-1.20 (1H, m), 1.45 (9H, s), 1.65-1.75 (1H, m), 2.40-2.55 (1H, m),2.90 (1H, dd, J=17.6, 5.4 Hz), 3.12 (1H, dd, J=17.6, 8.3 Hz), 3.41 (1H,dd, J=11.2, 5.4 Hz), 3.75 (1H, dd, J=11.2, 7.8 Hz), 4.97 (1H, d, J=14.2Hz), 5.01 (1H, d, J=14.2 Hz), 7.30-7.40 (5H, m)

REFERENCE EXAMPLE J1-Benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine (Isomer A)

[0169] To 50 ml of an ethanol solution of 1.70 g (5.13 mmol) of1-benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine-2-thione(isomer A) was added 14 ml of Raney nickel, followed by stirring at roomtemperature for 1.5 hours. Any insoluble matter was removed byfiltration, and the solvent was evaporated under reduced pressure.Chloroform was added to the residue, and the mixture was washed with 10%aqueous ammonia. The organic layer was dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure to give1.479 g (95.7%) of the title compound (isomer A) as a pale yellow oilysubstance.

[0170]¹H-NMR (CDCl₃) δ ppm: 0.85-0.95 (2H, m), 1.20-1.30 (1H, m), 1.44(9H, s), 1.50-1.65 (2H, m), 1.85-1.95 (1H, m), 2.10-2.25 (1H, m), 2.40(1H, dd, J=8.8, 5.9 Hz), 2.51 (1H, q, J=7.8 Hz), 2.62 (1H, dt, J=8.8,5.4 Hz), 2.72 (1H, t, J=8.7 Hz), 3.59 (1H, d, J=12.7 Hz), 3.62 (1H, d,J=12.7 Hz), and 7.20-7.40 (5H, m).

REFERENCE EXAMPLE K1-Benzyloxycarbonyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine(Isomer A)

[0171] To 30 ml of a dichloromethane solution of 1.466 g (4.86 mmol) of1-benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine (isomer A) wasadded 1.39 ml (9.72 mmol) of benzyl chloroformate at room temperature,and the mixture was stirred at the same temperature for 15.5 hours,followed by heat-refluxing for 1 hour. To the reaction mixture wasfurther added 0.70 ml (4.86 mmol) of benzyl chloroformate, followed byheat-refluxing for 1.5 hours. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=7:3) to give 1.261 g (75.1%) of thetitle compound as a colorless oily substance.

[0172]¹H-NMR (CDCl₃) δ ppm: 0.90-1.00 (2H, m), 1.05-1.15 (1H, m), 1.46(9H, s), 1.60-1.70 (2H, m), 1.80-1.95 (1H, m), 2.20-2.30 (1H, m),3.15-3.30 (1H, m), 3.30-3.40 (1H, m), 3.50-3.70 (2H, m), 5.14 (2H, s),and 7.25-7.40 (5H, m).

REFERENCE EXAMPLE L1-Benzyloxycarbonyl-3-(cis-2-t-butoxycarbonylaminocyclopropyl)pyrrolidine(Isomer A)

[0173] To 10 ml of a dichloromethane solution of 1.252 g (3.62 mmol) of1-benzyloxycarbonyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine wasadded 5 ml of trifluoroacetic acid under cooling with ice, and themixture was stirred at room temperature for 2 hours. After completion ofthe reaction, the solvent was removed by evaporation under reducedpressure. Toluene was added to the residue, followed by evaporation toobtain a crude carboxylic acid.

[0174] To 30 ml of a 2-methyl-2-propanol solution of the resulting crudecarboxylic acid were added 0.781 ml (3.62 mmol) of diphenylphosphoricacid azide and 0.758 ml (5.43 mmol) of triethylamine, and the mixturewas stirred at room temperature for 1 hour and then heated under refluxfor 31 hours. After completion of the reaction, the solvent wasevaporated under reduced pressure, and ethyl acetate was added to theresidue. The mixture was washed successively with a 5% citric acidaqueous solution, a saturated sodium carbonate aqueous solution, and asaturated sodium chloride aqueous solution. The organic layer was driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=7:3) to give 6.67 g (64.1%) ofethyl 3-(cis-2-t-butoxycarbonylcyclopropyl)-3-oxopropionate as a yellowoily substance and 575.2 mg (44.0%) of1-benzyloxycarbonyl-3-(cis-2-t-butoxycarbonylaminocyclopropyl)pyrrolidine(isomer A) as a colorless oily substance.

[0175]¹H-NMR (CDCl₃) δ ppm: 0.20-0.30 (1H, m), 0.75-0.95 (2H, m), 1.44(9H, s), 1.70-1.90 (2H, m), 2.00-2.10 (1H, m), 2.65-2.75 (1H, m),3.15-3.30 (1H, m), 3.30-3.40 (1H, m), 3.50-3.65 (2H, m), 4.50-4.65 (1H,brs), 5.13 (2H, s), and 7.30-7.40 (5H, m).

REFERENCE EXAMPLE M3-(Cis-2-t-butoxycarbonylaminocyclopropyl)pyrrolidine (Isomer A)

[0176] To 15 ml of an ethanol solution of 547.3 mg (1.52 mmol) of1-benzyloxycarbonyl-3-(cis-2-t-butoxycarbonylaminocyclopropyl)pyrrolidine(isomer A) was added 550 mg of 5% palladium-on-carbon, followed byshaking in a hydrogen stream (4 kg/cm²) for 1.5 hours. The catalyst wasremoved by filtration, and the solvent was removed by evaporation underreduced pressure to give 343.6 mg (quantitative) of the title compoundas a brown oily substance.

[0177]¹H-NMR (CDCl₃) δ ppm: 0.20-0.30 (1H, m), 0.75-0.95 (2H, m), 1.45(9H, s), 1.55-1.75 (2H, m), 1.90-2.00 (1H, m), 2.60-2.70 (1H, m),2.70-2.80 (1H, m), 2.90-3.00 (1H, m), 3.00-3.15 (2H, m), and 4.70-4.80(1H, brs).

REFERENCE EXAMPLE N1-Benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine-2-thione(Isomer B)

[0178] To 30 ml of a toluene solution of 1.534 g (4.86 mmol) of1-benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidin-2-one (isomerB) was added 1.062 g (2.62 mmol) of a Lawson's reagent, followed bystirring at 50 to 60° C. for 1.5 hours. After completion of thereaction, the reaction mixture was subjected to silica gel columnchromatography (hexane:ethyl acetate=7:3) to give 1.198 g (74.3%) of thetitle compound as a pale yellow solid.

[0179]¹H-NMR (CDCl₃) δ ppm: 0.90-1.00 (1H, m), 1.00-1.10 (1H, m),1.10-1.20 (1H, m), 1.35 (9H, s), 1.55-1.65 (1H, m), 2.40-2.50 (1H, m),2.97 (1H, dd, J=18.1, 6.3 Hz), 3.25-3.35 (2H, m), 3.52 (1H, dd, J=11.2,6.8 Hz), 4.92 (1H, d, J=14.2 Hz), 5.01 (1H, d, J=14.2 Hz), 7.25-7.40(5H, m).

REFERENCE EXAMPLE O1-Benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine (Isomer B)

[0180] To 50 ml of an ethanol solution of 1.19 g (3.59 mmol) of1-benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine-2-thione(isomer B) was added 10 ml of Raney nickel, followed by stirring at roomtemperature for 30 minutes. The insoluble matter was filtered off, andthe solvent was evaporated under reduced pressure. Chloroform was addedto the residue, and the mixture was washed with 10% aqueous ammonia. Theorganic layer was dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure to give 929.0 mg (85.8%) of thetitle compound as a pale yellow oily substance.

[0181]¹H-NMR (CDCl₃) δ ppm: 0.85-0.95 (2H, m), 1.15-1.30 (1H, m), 1.38(9H, s), 1.55-1.70 (2H, m), 2.05-2.25 (2H, m), 2.25-2.35 (1H, m),2.50-2.75 (3H, m), 3.56 (1H, d, J=12.7 Hz), 3.60 (1H, d, J=12.7 Hz), and7.20-7.40 (5H, m).

REFERENCE EXAMPLE P1-Benzyloxycarbonyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine(Isomer B)

[0182] To 15 ml of a dichloromethane solution of 922.6 mg (3.06 mmol) of1-benzyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine (isomer B) wasadded 0.874 ml (6.12 mmol) of benzyl chloroformate at room temperature,followed by stirring at the same temperature overnight. To the reactionmixture was further added 0.502 ml (3.52 mmol) of benzyl chloroformate,followed by stirring for 2 days. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate=7:3) to give 685.5 mg (64.8%) ofthe title compound as a colorless oily substance.

[0183]¹H-NMR (CDCl₃) δ ppm: 0.90-1.15 (3H, m), 1.43, 1.46 (9H, s each),1.60-1.80 (2H, m), 2.00-2.15 (1H, m), 2.20-2.30 (1H, m), 3.05-3.20 (1H,m), 3.30-3.50 (2H, m), 3.50-3.65 (1H, m), 5.10-5.20 (2H, m), and7.25-7.40 (5H, m).

REFERENCE EXAMPLE Q1-Benzyloxycarbonyl-3-(cis-2-t-butoxycarbonylaminocyclopropyl)pyrrolidine(Isomer B)

[0184] To 3 ml of a dichloromethane solution of 685.5 mg (1.98 mmol) of1-benzyloxycarbonyl-3-(cis-2-t-butoxycarbonylcyclopropyl)pyrrolidine(isomer B) was added 3 ml of trifluoroacetic acid under cooling withice, followed by stirring at room temperature for 1.5 hours. Aftercompletion of the reaction, the solvent was evaporated under reducedpressure, and toluene was added to the residue, followed by evaporationto obtain a crude carboxylic acid.

[0185] To 20 ml of a 2-methyl-2-propanol solution of the resulting crudecarboxylic acid were added 0.411 ml (1.98 mmol) of diphenylphosphoricacid azide and 0.399 ml (2.97 mmol) of triethylamine, and the mixturewas stirred at room temperature for 1.5 hours and then heated underreflux for 16 hours. After completion of the reaction, the solvent wasremoved by evaporation under reduced pressure, and ethyl acetate wasadded to the residue. The mixture was washed successively with a 5%citric acid aqueous solution, a saturated sodium carbonate aqueoussolution, and a saturated sodium chloride aqueous solution. The organiclayer was dried over anhydrous sodium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography (hexane:ethyl acetate=7:3) to give 345.2 mg(48.3%) of the title compound as a colorless oily substance.

[0186]¹H-NMR (CDCl₃) δ ppm: 0.20-0.35 (1H, m), 0.75-0.85 (1H, m),0.90-1.00 (1H, m), 1.40 (9H, s), 1.70-1.85 (2H, m), 1.95-2.10 (1H, m),2.60-2.70 (1H, m), 3.10-3.25 (1H, m), 3.30-3.40 (1H, m), 3.50-3.70 (2H,m), 4.50-4.65 (1H, brs), 5.05-5.20 (2H, m), and 7.25-7.40 (5H, m).

REFERENCE EXAMPLE R3-(Cis-2-t-butoxycarbonylaminocyclopropyl)pyrrolidine (Isomer B)

[0187] To 10 ml of an ethanol solution of 340.4 mg (0.94 mmol) of1-benzyloxycarbonyl-3-(cis-2-t-butoxycarbonylaminocyclopropyl)pyrrolidinewas added 350 mg of 5% palladium-on-carbon, and the mixture was shakenin a hydrogen stream (3.5 kg/cm²) for 1.5 hours. The catalyst wasremoved by filtration, and the solvent was evaporated under reducedpressure to give 213.0 mg (99.7%) of the title compound as a colorlesssolid.

[0188]¹H-NMR (CDCl₃) δ ppm: 0.20-0.30 (1H, m), 0.75-1.00 (2H, m), 1.45(9H, s), 1.60-1.80 (2H, m), 1.90-2.05 (1H, m), 2.60-2.80 (2H, m),2.80-3.20 (3H, m), and 4.65-4.80 (1H, m).

REFERENCE EXAMPLE S (1S,2R)-t-ButylCis-2-methoxycarbonylcyclopropanecarboxylate

[0189] To 120 ml of anhydrous tetrahydrofuran solution of 11.38 g (79.0mmol) of (−)-(1S,2R)-2-methoxycarbonylcyclopropanecarboxylic acid wereadded 1.93 g (15.80 mmol) of dimethylaminopyridine and 22.41 g (102.67mmol) of di-t-butyl dicarbonate at room temperature, and the mixture wasstirred at the same temperature for 18 hours. After completion of thereaction, the solvent was evaporated under reduced pressure, and ethylacetate was added to the residue. The mixture was washed successivelywith 0.5N hydrochloric acid, water, and a saturated sodium chlorideaqueous solution. The organic layer was dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure to give15.81 g (quantitative) of the title compound as a brown oily substance.

[0190]¹H-NMR (CDCl₃) δ ppm: 1.17 (1H, dt, J=8.3, 4.9 Hz), 1.44 (9H, s),1.55-1.65 (1H, m), 1.95-2.05 (2H, m), and 3.69 (3H, s).

REFERENCE EXAMPLE T (1R,2S)-Cis-2-t-butoxycarbonylcyclopropanecarboxylicAcid

[0191] To 150 ml of a methanol solution of 15.81 g (79.0 mmol) of(1S,2R)-t-butyl2-methoxycarbonylcyclopropanecarboxylate was added 50 mlof an aqueous solution of 6.77 g (102.6 mmol) of potassium hydroxideunder ice-cooling, followed by stirring at room temperature overnight.After completion of the reaction, the solvent was removed by evaporationunder reduced pressure. Water was added to the residue, followed bywashing with diethyl ether. The aqueous solution was adjusted to a p of2 to 3 with concentrated hydrochloric acid and extracted with ethylacetate. The organic layer was dried over anhydrous sodium sulfate, andthe solvent was evaporated under reduced pressure to give 14.71 g(quantitative) of the title compound as a pale yellow solid.

[0192]¹H-NMR (CDCl₃) δ ppm: 1.25-1.35 (1H, m), 1.44 (9H, s), 1.60-1.65(1H, m), and 2.00-2.10 (2H, m).

REFERENCE EXAMPLE U Ethyl3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]-3-oxopropionate

[0193] To 170 ml of an anhydrous tetrahydrofuran solution of 14.71 g(79.0 mmol) of (1R,2S)-2-t-butoxycarbonylcyclopropanecarboxylic acid wasadded 16.49 g (90.6 mmol) of 1,1-carbonyldiimidazole under cooling withice, and the mixture was stirred at room temperature for 1.5 hours. Thesolvent was removed by evaporation under reduced pressure. To 60 ml ofan anhydrous tetrahydrofuran solution of the resulting residue was added150 ml of an anhydrous tetrahydrofuran solution of 197.5 mmol ofpreviously prepared magnesium monoethyl malonate, followed by stirringfor 3 days. After completion of the reaction, the solvent was evaporatedunder reduced pressure. Ethyl acetate was added to the residue, and themixture was washed successively with 0.5N hydrochloric acid, a saturatedsodium hydrogencarbonate aqueous solution, and a saturated sodiumchloride aqueous solution. The organic layer was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography(hexane:ethyl acetate=7:3) to give 18.53 g (91.8%) of the title compoundas a colorless oily substance.

[0194]¹H-NMR (CDCl₃) δ ppm: 1.15-1.30 (4H, m), 1.42 (9H, s), 1.65-1.75(1H, m), 2.00-2.10 (1H, m), 2.25-2.35 (1H, m), 3.50-3.65 (2H, m), and4.15-5.25 (2H, m)

REFERENCE EXAMPLE V Ethyl3-[(1R,2S)-2-t-Butoxycarbonylcylcopropyl]acrylate

[0195] To 200 ml of a methanol solution of 18.48 g (72.1 mmol) of ethyl3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]-3-oxopropionate was added 1.36g (36.1 mmol) of sodium borohydride at −10° C., followed by stirring atthat temperature for 30 minutes. A saturated ammonium chloride aqueoussolution was added thereto, and the reaction mixture was extracted withchloroform. The organic layer was dried over anhydrous sodium sulfate,and the solvent was evaporated under reduced pressure to give 18.62 g(quantitative) of a crude alcohol as a colorless oily substance.

[0196] To 400 ml of a dichloromethane solution of 18.62 g (72.1 mmol) ofthe crude alcohol were added 20.10 ml (144.2 mmol) of triethylamine and7.25 ml (93.7 mmol) of methanesulfonyl chloride under cooling with ice.After stirring the mixture at the same temperature for 1.5 hours, 23.72ml (158.6 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added thereto,followed by stirring at room temperature for 15 hours. The solvent wasevaporated under reduced pressure, and chloroform was added to theresidue. The mixture was washed successively with 0.1N hydrochloricacid, water, and a saturated sodium chloride aqueous solution. Theorganic layer was dried over anhydrous sodium sulfate, and the solventwas evaporated under reduced pressure to give 17.33 g (quantitative) ofthe title compound as a yellow oily substance.

[0197]¹H-NMR (CDCl₃) δ ppm: 1.27 (3H, t, J=7.3 Hz), 1.25-1.35 (1H, m),1.35-1.45 (1H, m), 1.45 (9H, s), 1.90-2.05 (2H, m), 4.10-4.25 (2H, m),5.98 (1H, d, J=15.6 Hz), and 6.91 (1H, ddd, J=15.6, 8.8, 1.5 Hz)

REFERENCE EXAMPLE W Ethyl3-[(1R,2S)-2-t-Butoxycarbonylcyclopropyl]-3-nitroethylpropionate

[0198] To 150 ml of a nitromethane solution of 17.33 g (72.1 mmol) ofethyl 3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl)acrylate was added 14.47ml (115.4 mmol) of tetramethylguanidine at room temperature, and themixture was stirred at 70° C. for 3.5 hours. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=85:15) to give 18.95 g(87.2%) of the title compound as a colorless oily substance.

[0199]¹H-NMR (CDCl₃) δ ppm: 0.95-1.15 (2H, m), 1.25-1.35 (4H, m), 1.46and 1.48 (9H, s each), 1.65-1.80 (1H, m), 2.40-2.70 (2H, m), 2.70-2.85(1H, m), 4.10-4.20 (2H, m), and 4.45-4.55 and 4.60-4.75 (2H, m each).

REFERENCE EXAMPLE X3-[(1R,2S)-2-t-Butoxycarbonylcyclopropyl)pyrrolidin-2-one

[0200] To 600 ml of a methanol solution of 18.99 g (63.0 mmol) of ethyl3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]-3-nitroethylpropionate wereadded about 5 g of 10% palladium-on-carbon, 7 g of 5%palladium-on-carbon, and 51.67 g (819 mmol) of ammonium formate at roomtemperature, and the mixture was stirred at the same temperature for 4hours. After completion of the reaction, the solvent was evaporatedunder reduced pressure. Water was added to the residue, followed byextraction with chloroform. The organic layer was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure togive 14.67 g (85.8%) of a crude amine.

[0201] A toluene solution (500 ml) of 14.67 g of the resulting crudeamine was heated at 110 to 120° C. for 1.5 hours. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (chloroform:methanol=98:2) to give10.38 g of a mixture of3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]pyrrolidin-2-one and3-[1R,2S)-2-t-butoxycarbonylcylcopropyl]-1-hydroxypyrrolidin-2-one and2.08 g of3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]-1-hydroxypyrrolidin-2-one ascolorless crystals.

[0202] To 100 ml of a solution of 1.85 g of the resulting3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]-1-hydroxypyrrolidin-2-one in a3:1 mixed solvent of methanol and water was added 4.45 ml of a titaniumtrichloride solution at room temperature while maintaining the reactionmixture neutral by addition of a 1N sodium hydroxide aqueous solution,followed by stirring at the same temperature for 1.5 hours. Aftercompletion of the reaction, water was added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The organic layer wasdried over anhydrous sodium sulfate, and the solvent was evaporatedunder reduced pressure to give 1.53 g (88.4%) of3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]pyrrolidin-2-one.

[0203] In the same manner, 7.30 g of3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]pyrrolidin-2-one was obtainedfrom 9.49 g of the mixture of3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]pyrrolidin-2-one and3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]-1-hydroxypyrrolidin-2-one.

[0204]¹H-NMR (CDCl₃) δ ppm: 0.95-1.10 (2H, m), 1.20-1.35 (1H, m), 1.45(9H, s), 1.65-1.75 (1H, m), 2.05-2.60 (3H, m), 3.10-3.20, 3.20-3.30 (1H,m each), 3.35-3.45, 3.55-3.65 (1H, m each), and 5.90-6.10 (1H, m).

REFERENCE EXAMPLE Y1-Benzyl-3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]pyrrolidon-2-one

[0205] A solution (100 ml) of 8.816 g (39.1 mmol) of3-[(1R,2S)-2-t-butoxycarbonylcylcopropyl]pyrrolidin-2-one in a 3:2 mixedsolvent of tetrahydrofuran and dimethylformamide was added dropwise to20 ml of a suspension of 1.72 g (43.0 mmol) of sodium hydride indimethylformamide while cooling with ice, and the mixture was stirred atroom temperature for 1.5 hours. Then, 40 ml of a tetrahydrofuransolution of 6.76 ml (58.7 mmol) of benzyl chloride was added dropwisethereto, followed by stirring for 3 hours. After completion of thereaction, a saturated ammonium chloride aqueous solution was addedthereto, followed by evaporation under reduced pressure. Water was addedto the residue, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and then with a saturated sodiumchloride aqueous solution. The organic layer was dried over anhydroussodium sulfate, and the solvent was evaporated under reduced pressure.The residue was purified by silica gel column chromatography(hexane:ethyl acetate=7:3) to give 5.710 g (44.8%) of1-benzyl-3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]pyrrolidin-2-one(isomer A¹) as a colorless solid. Then, the column was eluted with a 1:1mixed solvent of hexane and ethyl acetate to give 3.959 g (31.1%) of1-benzyl-3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]pyrrolidin-2-one(isomer B¹) as a pale yellow oily substance.

[0206] Isomer A¹:

[0207]¹H-NMR (CDCl₃) δ ppm: 0.85-1.00 (2H, m), 1.10-1.20 (1H, m), 1.45(9H, s), 1.65-1.75 (1H, m), 2.25 (1H, dd, J=16.1, 6.3 Hz), 2.35-2.45(1H, m), 2.50 (1H, dd, J=16.1, 8.8 Hz), 3.08 (1H, dd, J=9.8, 5.9 Hz),3.43 (1H, dd, J=9.8, 7.8 Hz), 4.45 (1H, d, J=14.7 Hz), 4.46 (1H, d,J=14.7 Hz), and 7.20-7.40 (5H, m)

[0208] Isomer B¹:

[0209]¹H-NMR (CDCl₃) δ ppm: 0.90-1.00 (1H, m), 1.00-1.05 (1H, m),1.10-1.25 (1H, m), 1.37 (9H, s), 1.55-1.65 (1H, m), 2.33 (1H, dd,J=16.1, 7.3 Hz), 2.35-2.50 (1H, m), 2.67 (1H, dd, J=16.1, 8.3 Hz), 2.99(1H, dd, J=9.8, 6.3 Hz), 3.21 (1H, dd, J=9.8, 7.8 Hz), 4.40 (1H, d,J=14.7 Hz), 4.48 (1H, d, J=14.7 Hz), and 7.20-7.40 (5H, m)

[0210] [α]_(D) ²²+75.980 (c=1.045, CHCl₃)

REFERENCE EXAMPLE Z1-Benzyl-3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]pyrrolidine-2-thione(Isomer B¹)

[0211] To 80 ml of a toluene solution of 3.999 g (12.69 mmol) of1-benzyl-3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]pyrrolidin-2-one(isomer B¹) was added 2.769 g (6.85 mmol) of a Lawson's reagent, and themixture was stirred at 50 to 60° C. for 1 hour and 40 minutes. Aftercompletion of the reaction, the reaction mixture was subjected to silicagel column chromatography (hexane:ethyl acetate=4:1) to give 4.044 g(96.2%) of the title compound as a pale yellow solid.

[0212]¹H-NMR (CDCl₃) δ ppm: 0.90-1.00 (1H, m), 1.00-1.10 (1H, m),1.10-1.20 (1H, m), 1.35 (9H, s), 1.55-1.65 (1H, m), 2.40-2.55 (1H, m),2.97 (1H, dd, J=17.6, 6.4 Hz), 3.25-3.35 (2H, m), 3.52 (1H, dd, J=11.2,7.8 Hz), 4.92 (1H, d, J=14.2 Hz), 5.01 (1H, d, J=14.2 Hz), and 7.25-7.40(5H, m).

REFERENCE EXAMPLE AA1-Benzyl-3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]pyrrolidine (IsomerB¹)

[0213] To 60 ml of an ethanol solution of 4.040 g (12.19 mmol) of1-benzyl-3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]pyrrolidine-2-thione(isomer B¹) was added 20 ml of Raney nickel, followed by stirring atroom temperature for 40 minutes. Any insoluble matter was removed byfiltration, and the solvent was evaporated under reduced pressure.Chloroform was added to the residue, and the mixture was washed with 10%aqueous ammonia. The organic layer was dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure to give2.988 g (81.3%) of the title compound as a colorless oily substance.

[0214]¹H-NMR (CDCl₃) δ ppm: 0.85-1.00 (2H, m), 1.15-1.30 (1H, m), 1.38(9H, s), 1.55-1.70 (2H, m), 2.00-2.25 (2H, m), 2.30 (1H, dd, J=9.3, 5.9Hz), 2.50-2.65 (3H, m), 3.56 (1H, d, J=12.7 Hz), 3.60 (1H, d, J=12.7Hz), and 7.20-7.35 (5H, m).

REFERENCE EXAMPLE BB1-Benzyloxycarbonyl-3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]pyrrolidine(Isomer B¹)

[0215] To 50 ml of a dichloromethane solution of 2.984 g (9.90 mmol) of1-benzyl-3-[(1R,2S )-2-t-butoxycarbonylcyclopropyl]pyrrolidine (isomerB¹) was added 2.83 ml (19.82 mmol) of benzyl chloroformate at roomtemperature, and the mixture was stirred at the same temperature for 14hours. To the reaction mixture was further added 1.98 ml (13.86 mmol) ofbenzyl chloroformate, followed by refluxing for 2 hours. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (hexane:ethyl acetate=7:3) to give2.188 g (64.0%) of the title compound as a colorless oily substance.

[0216]¹H-NMR (CDCl₃) δ ppm: 0.90-1.05 (2H, m), 1.05-1.15 (1H, m), 1.43and 1.46 (9H, s each), 1.60-1.80 (2H, m), 2.00-2.15 (1H, m), 2.20-2.30(1H, m), 3.05-3.20 (1H, m), 3.30-3.40 (1H, m), 3.40-3.50 (1H, m),3.50-3.65 (1H, m), 5.05-5.20 (2H, m), and 7.25-7.40 (5H, m).

REFERENCE EXAMPLE CC1-Benzyloxycarbonyl-3-[(1S,2S)-2-t-butoxycarbonylaminocyclopropyl]pyrrolidine(Isomer B¹)

[0217] To 10 ml of a dichloromethane solution of 2.183 g (6.32 mmol) of1-benzyloxycarbonyl-3-[(1R,2S)-2-t-butoxycarbonylcyclopropyl]pyrrolidine(isomer B¹) was added 8 ml of trifluoroacetic acid under cooling withice, and the mixture was stirred at room temperature for 1.5 hours.After completion of the reaction, the solvent was evaporated underreduced pressure. Toluene was added to the residue and evaporated underreduced pressure to obtain a crude carboxylic acid.

[0218] To 60 ml of a solution of the resulting crude carboxylic acid in2-methyl-2-propanol were added 1.36 ml (6.32 mmol) of diphenylphosphoricacid azide and 1.32 ml (9.48 mmol) of triethylamine, and the mixture wasstirred at room temperature for 1.5 hours and then heated under refluxfor 35 hours. After completion of the reaction, the solvent wasevaporated under reduced pressure. Ethyl acetate was added to theresidue, and the mixture was washed successively with a 5% citric acidaqueous solution, a saturated sodium carbonate aqueous solution, and asaturated sodium chloride aqueous solution. The organic layer was driedover anhydrous sodium sulfate, and the solvent was evaporated underreduced pressure. The resulting residue was purified by silica gelcolumn chromatography (hexane:ethyl acetate=7:3) to give 950.3 mg(41.7%) of the title compound as a colorless oily substance.

[0219]¹H-NMR (CDCl₃) δ ppm: 0.20-0.35 (1H, m), 0.75-0.90 (1H, m),0.90-1.00 (1H, m), 1.40 (9H, s), 1.70-1.85 (2H, m), 1.95-2.10 (1H, m),2.60-2.70 (1H, m), 3.15-3.25 (1H, m), 3.30-3.40 (1H, m), 3.50-3.70 (2H,m), 4.50-4.65 (1H, brs), 5.05-5.15 (2H, m), and 7.25-7.40 (5H, m).

[0220] [α]_(D) ²³+36.820 (c=1.950, CHCl₃)

REFERENCE EXAMPLE DD3-[(1S,2S)-2-t-Butoxycarbonylaminocyclopropyl]pyrrolidine (Isomer B¹)

[0221] To 25 ml of an ethanol solution of 911.3 mg (2.53 mmol) of1-benzyloxycarbonyl-3-[(1S,2S)-2-t-butoxycarbonylaminocyclopropyl]pyrrolidine(isomer B¹) was added 900 mg of 5% palladium-on-carbon, and the mixturewas shaken in a hydrogen stream (4.5 kg/cm²) for 1.5 hours. To thereaction mixture was added 100 mg of 5% palladium-on-carbon, followed byshaking in a hydrogen stream (4.0 kg/cm²) for 1 hour. The catalyst wasremoved by filtration, and the solvent was removed by evaporation underreduced pressure to give 572.2 mg (quantitative) of the title compoundas a colorless solid.

[0222]¹H-NMR (CDCl₃) δ ppm: 0.20-0.30 (1H, m), 0.80-1.00 (2H, m), 1.45(9H, s), 1.65-1.85 (2H, m), 2.y00-2.10 (1H, m), 2.60-2.70 (1H, m),2.80-2.95 (1H, m), 2.95-3.10 (1H, m), 3.15-3.25 (2H, m), 4.75-4.95 (1H,m).

[0223] The antimicrobial activity of the compound prepared in Example 3is shown in Table 1 below. TABLE 1 Antimicrobial Spectra MicroorganismMIC (μg/mL) E. coli, NIHJ ≦0.003 S. flexneli, 2A 5503 ≦0.003 Pr.vulgaris, 08601 0.05 Pr. mirabilis, IFO-3849 0.05 Ser. marcescens, 101000.10 Ps. aeruginosa, 32104 0.20 Ps. aeruginosa, 32121 0.10 Ps.maltophilia, IID-1275 0.05 S. aureaus, 209P ≦0.003 S. epidermidis, 565000.006 Str. pyopenes, G-36 0.006 Str. faecalis, ATCC-19433 0.025 S.aureus, 870307 0.025

Industrial Applicability

[0224] The compound according to the present invention exhibitsexcellent activity and safety and is useful as an antimicrobial agent.

1. A compound represented by formula (I):

wherein R¹ and R² each independently represents a hydrogen atom or analkyl group having 1 to 6 carbon atoms which may be substituted with oneor more substituents selected from the group consisting of a hydroxylgroup, a halogen atom, an alkylthio group having 1 to 6 carbon atoms,and an alkyloxy group having 1 to 6 carbon atoms; n represents aninteger of 1 to 3; Q represents a partial structure having formula:

wherein R³ represents an alkyl group having 1 to 6 carbon atoms, analkenyl group having 2 to 6 carbon atoms, a halogenoalkyl group having 1to 6 carbon atoms, a substituted or unsubstituted cycloalkyl grouphaving 3 to 6 carbon atoms, a substituted or unsubstituted aryl group, asubstituted or unsubstituted heteroaryl group, an alkoxyl group having 1to 6 carbon atoms, or an alkylamino group having 1 to 6 carbon atoms; R⁴represents a hydrogen atom or an alkylthio group having 1 to 6 carbonatoms; R³ and R⁴ may be taken together with part of the mother skeletonto which they are bonded to form a cyclic structure that may contain asulfur atom as a ring constituting atom and/or may be substituted withan alkyl group having 1 to 6 carbon atoms; R⁵ represents a hydrogenatom, an amino group, a hydroxyl group, a thiol group, a halogenomethylgroup, an alkyl group having 1 to 6 carbon atoms, an alkenyl grouphaving 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atomsor an alkoxyl group having 1 to 6 carbon atoms, in which the amino groupmay be substituted with one or more substituents selected from the groupconsisting of a formyl group, an alkyl group having 1 to 6 carbon atoms,and an acyl group having 2 to 5 carbon atoms; X¹ represents a halogenatom or a hydrogen atom; and A represents a nitrogen atom or a partialstructure represented by formula (II):

wherein X² represents a hydrogen atom, an amino group, a halogen atom, acyano group, a halogenomethyl group, a halogenomethoxyl group, an alkylgroup having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbonatoms, an alkynyl group having 2 to 6 carbon atoms, or an alkoxyl grouphaving 1 to 6 carbon atoms, in which the amino group may be substitutedwith one or more substituents selected from the group consisting of aformyl group, an alkyl group having 1 to 6 carbon atoms and an acylgroup having 2 to 5 carbon atoms; and X² and R³ may be taken togetherwith part of the mother skeleton to which they are bonded to form acyclic structure that may contain an oxygen atom, a nitrogen atom or asulfur atom as a ring constituting atom and/or may be substituted withan alkyl group having 1 to 6 carbon atoms; and Y represents a hydrogenatom, a phenyl group, an acetoxymethyl group, a pivaloyloxymethyl group,an ethoxycarbonyl group, a choline group, a dimethylaminoethyl group, a5-indanyl group, a phthalidinyl group, a5-alkyl-2-oxo-1,3-dioxol-4-ylmethyl group, a 3-acetoxy-2-oxobutyl group,an alkyl group having 1 to 6 carbon atoms, an alkoxymethyl group having2 to 7 carbon atoms, or a phenylalkyl group having 1 to 6 carbon atomsin the alkyl moiety thereof; and the two substituents on thecyclopropane ring,

are in a cis-configuration, or a salt or hydrate thereof or a hydrate ofthe salt.
 2. A compound according to claim 1, wherein Q in formula (I)is a partial structure represented by formula:

wherein R³, R⁴, R⁵, X¹, X², and Y are as defined above, or a salt orhydrate thereof or a hydrate of the salt.
 3. A compound according toclaim 1 or 2, wherein Q in formula (I) isa6-carboxy-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazin-10-ylgroup, or a salt or hydrate thereof or a hydrate of the salt.
 4. Acompound according to claim 1 or 2, wherein Q in formula (I) is a8-amino-6-carboxy-9-fluoro-2,3-dihydro-3-(S)-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]benzoxazin-10-ylgroup, or a salt or hydrate thereof or a hydrate of the salt.
 5. Acompound according to claim 1 or 2, wherein Q in formula (I) is a5-amino-3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxyl-4-oxoquinolin-7-ylgroup, or a salt or hydrate thereof or a hydrate of the salt.
 6. Acompound according to claim 1 or 2, wherein Q in formula (I) is a5-amino-3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methyl-4-oxoquinolin-7-ylgroup, or a salt or hydrate thereof or a hydrate of the salt.
 7. Acompound according to claim 1 or 2, wherein Q in formula (I) is a3-carboxy-6-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxyl-4-oxoquinolin-7-ylgroup, or a salt or hydrate thereof or a hydrate of the salt.
 8. Acompound according to claim 1, 2, 3, 4, 5, 6 or 7, wherein n in formula(I) is 2, or a salt or hydrate thereof or a hydrate of the salt.
 9. Acompound according to claim 1, 2, 3, 4, 5, 6, 7 or 8, wherein both R¹and R² in formula (I) are a hydrogen atom, or a salt or hydrate thereofor a hydrate of the salt.
 10. A compound according to claim 1, 2, 8 or9, wherein R³ in formula (I) is a halogenocyclopropyl group, or a saltor hydrate thereof or a hydrate of the salt.
 11. A compound according toclaim 1, 2, 8 or 9, wherein R³ in formula (I) is a1,2-cis-2-halogenocyclopropyl group, or a salt or hydrate thereof or ahydrate of the salt.
 12. A compound according to claim 1, 2, 8, 9, 10 or11, wherein R³ in formula (I) is a stereochemically pure substituent, ora salt or hydrate thereof or a hydrate of the salt.
 13. A compoundaccording to claim 1, 2, 8 or 9, wherein R³ in formula (I) is a(1R,2S)-2-halogenocyclopropyl group, or a salt or hydrate thereof or ahydrate of the salt.
 14. A compound according to claim 1, 2, 8, 9, 10 or11, wherein R³ in formula (I) is a (1R,2S)-2-fluorocyclopropyl group, ora salt or hydrate thereof or a hydrate of the salt.
 15. A compoundaccording to claim 1, 2, 8, 9, 10, 11, 12, 13 or 14, wherein X¹ informula (I) is a halogen atom, or a salt or hydrate thereof or a hydrateof the salt.
 16. A compound according to claim 1, 2, 8, 9, 10, 11, 12,13, 14 or 15, wherein X¹ in formula (I) is a fluorine atom, or a salt orhydrate thereof or a hydrate of the salt.
 17. A compound according toclaim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16, whereinthe compound of formula (I) is a stereochemically pure compound, or asalt or hydrate thereof or a hydrate of the salt. 18.5-Amino-7-{3-[(1S,2S)-2-aminocyclopropyl]-1-pyrrolidinyl}-6-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid or a salt or hydrate thereof or a hydrate of the salt.
 19. A drugcontaining any of the compounds described in claims 1 to 18, hydratesthereof, salts thereof, and hydrates of the salts as an activeingredient.
 20. An antimicrobial agent containing any of the compoundsdescribed in claims 1 to 18, hydrates thereof, salts thereof, andhydrates of the salts as an active ingredient.
 21. A compoundrepresented by formula (VI):

wherein R¹ and R² each independently represents a hydrogen atom or analkyl group having 1 to 6 carbon atoms which may be substituted with oneor more substituents selected from the group consisting of a hydroxylgroup, a halogen atom, an alkylthio group having 1 to 6 carbon atoms,and an alkyloxy group having 1 to 6 carbon atoms; one of R¹ and R² maybe a protective group for amino group; n represents an integer of 1 to3; Q′ represents a hydrogen atom or a protective group for amino group;and the two substituents on the cyclopropane ring,

are in a cis-configuration; or a salt or hydrate thereof or a hydrate ofthe salt.
 22. A compound according to claim 21, wherein the protectivegroup for amino group is selected from the group consisting of analkoxylcarbonyl group, an aralkyloxycarbonyl group, an acyl group, analkyl group, an aralkyl group, and a substituted silyl group, or a saltor hydrate thereof or a hydrate of the salt.
 23. A compound according toclaim 21 or 22, wherein the protective group for amino group is selectedfrom the group consisting of a t-butoxycarbonyl group, a2,2,2-trichloroethoxycarbonyl group, a benzyloxycarbonyl group, ap-methoxybenzyloxycarbonyl group, a p-nitrobenzyloxycarbonyl group, anacetyl group, a methoxyacetyl group, a trifluoroacetyl group, achloroacetyl group, a pivaloyl group, a formyl group, a benzoyl group, at-butyl group, a benzyl group, a p-nitrobenzyl group, a p-methoxybenzylgroup, a triphenylmethyl group, a methoxymethyl group, a t-butoxymethylgroup, a tetrahydropyranyl group, a 2,2,2-trichloroethoxymethyl group, atrimethylsilyl group, an isopropyldimethylsilyl group, at-butyldimethylsilyl group, a tribenzylsilyl group, and at-butyldiphenylsilyl group, or a salt or hydrate thereof or a hydrate ofthe salt.
 24. A compound according to claim 21, 22 or 23, wherein Q′ andone of R¹ and R² are different protective group for amino groups, or asalt or hydrate thereof or a hydrate of the salt.
 25. A compoundaccording to claim 21, 22, 23 or 24, wherein the compound of formula(VI) is a stereochemically pure compound, or a salt or hydrate thereofor a hydrate of the salt. 26.1-Benzyloxycarbonyl-3-[(1S,2S)-2-t-butoxycarbonylaminocyclopropyl]pyrrolidine.